Quorum sensing (QS) is a method of intercellular communication in certain microorganisms which assesses local population density and coordinates the expression of phenotypes beneficial to the microorganism population. QS involves the release of a chemical signal, typically a small molecule or peptide autoinducer, into the environment at a concentration proportional to cell density. At a threshold signal concentration, the autoinducer binds a cognate receptor protein initiating changes in gene expression.
For example, the Gram-negative, opportunistic pathogen Pseudomonas aeruginosa uses QS to regulate biofilm formation, group motility, and various excreted virulence factors to overwhelm host defenses and establish chronic infections. Often these infections occur in immunocompromised individuals, for example, those having cystic fibrosis or HIV or suffering from chronic wounds.
Multidrug resistance to antibiotics is an emerging global threat and is a particular concern with pathogenic Pseudomonas strains and more particularly with Pseudomonas aeruginosa. In response to this threat, there has been increasing clinical interest in the development of antivirulence therapeutics with the development of chemical agents that can attenuate bacterial virulence phenotypes without generating a strong selective pressure to evolve resistance. QS circuits are particularly attractive targets for development of such chemical agents and anti-QS agents hold significant promise as resistance-robust drugs.
The exemplary Gram-negative bacterial, opportunistic pathogen Pseudomonas aeruginosa uses three interacting QS circuits—Las, Rhl, and Pq, see FIG. 1—to regulate the global expression of myriad virulence-associated genes. See: Welsh M. et al. (2015) for an overview of QS in P. aeruginosa. Interception of these signaling networks with small molecules represents an emerging strategy for the development of anti-infective agents against this bacterium. N-acyl L-homoserine lactones (AHLs) act as autoinducers for QS in the LasR and the RhlR circuits (natural autoinducers are illustrated in FIG. 1). The AHL signal is synthesized by a LuxI-type synthase and is recognized by an intracellular LuxR-type receptor. LasI and RhlI produce the autoinducers N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL) and N-butyryl-L-homoserine lactone (BHL), respectively. The native signals activate LasR and RhlR which homodimerize and act as transcription factors to regulate a specific set of genes. In turn, LasR and RhlR are repressed by the “orphan” LuxR-type receptor QscR, which also binds OdDHL. A third QS system in P. aeruginosa, Pqs, does not respond to AHLs, but to the autoinducer, 2-heptyl-3-hydroxy-4(1H)-quinolone, known as Pseudomonas quinolone signal (PQS). The LysR-type transcriptional regulator PqsR binds PQS and controls a separate regulon. Under standard laboratory conditions, Las induces expression of both the Rhl and Pqs systems. Once active, the Pqs system positively regulates Rhl and Rhl represses Pqs. Las has typically been viewed as the master regulator of the QS systems; however, studies have indicated that this regulatory scheme is nutritionally and environmentally dependent.
Many research groups have targeted the individual QS systems in P. aeruginosa to identify non-native small molecules and macromolecules that attenuate certain virulence phenotypes in the wild-type bacterium. Most studies have focused on LasR and reported compounds that inhibit LasR at low micromolar concentrations and reduce the production of various virulence factors, Muh et al. (2006), Amara et al. (2009), Hodgkinson et al. 2012, Geske et al. (2005), Geske et al. (2007), Geske et al. (2008a), Geske et al. (2008b), and Mattmann et al. (2011). See FIG. 2 for exemplary LasR inhibitors.
The present invention relates to certain compounds which exhibit potent and efficient inhibition of QS in Gram-negative bacteria, particularly of Pseudomonas strains and more particularly of P. aeruginosa strains.
U.S. published application US 2009/0123512 (May 2009) relates to QS modulators of formula:
where n is 3-13.
U.S. Pat. No. 7,659,409 relates to a method for synthesis of 3-hydroxy 3-(2-thienyl)propionamides which are reported to be useful as synthetic intermediates of pharmaceutical preparations and a method for obtaining optically active 3-amino-1-(2-thienyl)-l-propanols. The patent reports the asymmetric reduction of a compound of generic formula:
to produce compounds of formula:
whereR1 and R1′ each independently represents hydrogen, alkyl, aryl or aralkyl,R3 and R4 each independently represents hydrogen, or alkyl and may together form a carbon ring,R5 represents a halogen, nitro, hydroxyl, alkyl which may be substituted, an aryl group which may be substituted, or an alkoxy which may be substituted, andn is 0 to 3.
U.S. published patent application 2006/0264641 relates to a process for preparing enantiomer-enriched 3-heteroaryl-1-aminopropan-3-ols which are said to have industrial significance as intermediates for preparation of medicaments. The process involves reaction of a compound of formula:Heteroaryl-CO—CH2—W,where W is among others C(O)YR1n, where Y is oxygen and n is 1 or Y is nitrogen and n is 2; andeach R1 independently is hydrogen C1-C8 alkyl, C4-C10 aryl, or C5-C11-arylalkyl or when Y is N, the two R1 together are C3-C5 alkylene with certain amines in the presence of a microorganism.